According to the World Health Organization, mortality due to cancer is expected to increase from 7.6 million in 2008 to 12 million deaths in 2030. To address this growing problem, two emerging paradigms that are driving the evolution of newer treatment strategies are: (i) better understanding of oncogenic drivers, leading to the development of molecularly ‘targeted’ therapeutics; and, (ii) the use of nanotechnology to deliver drugs specifically to the tumor, thereby improving therapeutic index. However the interface between these two paradigms, which can offer unique opportunities for improving cancer chemotherapy, currently remains largely underexplored.
Paclitaxel, docetaxel and cabazitaxel are well known taxanes commonly used for the treatment of metastatic ovarian cancer and breast cancer. Their unique anti proliferative mechanism of action and broad range of activity were attracted by scientific community. Taxanes promote hyper stabilization of microtubules in dividing cell and thereby prevents the disassembly of microtubules necessary for cell division. Due to the high potency and non specificity towards cancer cell it shows serious undesired side effects like nausea, vomiting, diarrhea, dizziness, or drowsiness etc. Extreme insolubility in aqueous medium is another drawback and effective solvents like polyoxyethylated castor oil/ethanol and dilution with suitable buffer are used prior to administration which in addition provokes severe hypersensitive immune responses. To overcome the challenges of administration multiple approaches have been reported in literature. The improved formulation of paclitaxel in the form of micelles, liposome and emulsions1, 2 can overcome some pharmacokinetics profile but the drug partition out rapidly from the carrier in in vivo system. In some approaches the pharmacokinetics has been improved by synthesizing new taxane analogs with improved aqueous solubility2. Thus several taxane analogs3 have been synthesized to overcome these challenges and the solubility problems remain a major issue, potency gone down sharply and selectivity is not improved remarkably.
To address the formulation challenge and improved efficacy several hydrophobic4, lipophilic taxane5 prodrugs have been synthesized where enhance permeability and retention (EPR) phenomenon considered as effective drug accumulation method to tumor and hence better in vivo efficacy. The lipids used in those prodrugs include phospholipids, cholesterol, fatty acids etc.
Platinum-based chemotherapeutic agents are used as first line of therapy in over 70% of all cancers. Cisplatin undergoes rapid formation of cis-[Pt(NH3)2Cl(OH2)]+ and cis-[Pt(NH3)2(OH2)]2+ resulting in nephrotoxicity. Further, aquation of both carboplatin and oxaliplatin are significantly slower, resulting in decreased potency. In the recent past, considerable progress has been made wherein, Dhar et al (PNAS, 2008, 105, 17356) generated a platinum (IV) complex (c,t,c-[Pt(NH3)2(O2CCH2CH2CH2CH2CH3)2Cl2] that is hydrophobic enough for encapsulation into PLGA-b-PEG nanoparticles. However, the prodrug in this case has to be intracellularly processed into cisplatin. Furthermore, alternative strategies based on conjugation of platinum to polymers (eg a polyamidoamine dendrimer-platinum complex) resulted in a 200-550 fold reduction in cytotoxicity than free cisplatin. This was a result of strong bonds formed between the polymer and platinum (J Pharm Sci, 2009, 98, 2299). Another example is AP5280, a N-(2-hydroxypropyl) methacrylamide copolymer-bound platinum that is less potent than carboplatin. Here, the platinum is held by an aminomalonic acid chelating agent coupled to the COOH-terminal glycine of a tetrapeptide spacer (Clin Can Res, 2004, 10, 3386; Eur J Can, 2004, 40, 291).